Since its discovery in 1957, type I interferon has been recognized as the major antiviral cytokine in vertebrates. To combat viral infections, most nucleated vertebrate cells are able to both produce and respond to type I interferon. The antiviral function of type I interferon is carried out through its binding to the type I interferon receptor (IFNAR1), activation of the JAK/STAT pathway and subsequent induction of a large set of target genes important in antiviral responses On the other hand, as a result of co-evolution, different viruses have developed various strategies to inhibit the ability of host cells to either produce or respond to type I interferons. To understand this paradox of host and pathogen interactions, we seek to determine how host cells can recognize different viruses and howthis recognition event results in the production of type I interferons. We, together with other groups, have previously demonstrated that toll-like receptors (TLRs) can mediate type I interferon production and antiviral responses through activation of interferon regulatory factors, IRF3 and IRF7. While TLRs are able to recognize certain viral infections in innate immune cells such as macrophages and plasmacytoid dendritic cells (pDCs), additional intracellular receptors such as PKR and RIG-I are involved in type I interferon production in response to viral infections in non-immune cells. Our preliminary studies indicated that TNF receptor associated factor 3 (TRAF3) might be a critical modulator of type I interferon induction in both immune and non-immune cells during viral infection. The goal of this application is to further develop our functional as well as mechanistic understanding of the role of TRAF3 in host biodefense against infection by different types of viruses. In this research proposal, we will take advantage of TRAFS-deficient cells and mice to determine the antiviral functions of TRAF3, use biochemical approaches to dissect TRAFS-mediatedsignal transduction pathways, and also explore the contributions of the TRAFS-mediated pathways to interferon induction in response to infections with different types of viruses such as Influenza, Yellow Fever, Herpes Simplex, Ectromelia and Vesicular Stomatitis virus. We believe that our studies will provide significant insights into the mechanisms of type I interferon induction and potential novel therapeutic targets for improving our immune response against different types of viral infections.